浮米每周文献快讯为您总结全球知名药企在药物研究上的最新进展。本周共有8篇文献，详细内容下见。1. 原文标题及出处：Omarigliptin (MK-3102): A Novel Long-Acting DPP-4 Inhibitor for Once-Weekly Treatment of Type 2 Diabetes.
J. Med. Chem., 2014, 57 (8), pp 3205–3212
DOI: 10.1021/jm401992e
公司/组织：默克
候选药物化学结构式/活性：
靶点/作用机制：DDP-4抑制剂
摘要原文：
In our effort to discover DPP-4 inhibitors with added benefits over currently commercially available DPP-4 inhibitors, MK-3102 (omarigliptin), was identified as a potent and selective dipeptidyl peptidase 4 (DPP-4) inhibitor with an excellent pharmacokinetic profile amenable for once-weekly human dosing and selected as a clinical development candidate. This manuscript summarizes the mechanism of action, scientific rationale, medicinal chemistry, pharmacokinetic properties, and human efficacy data for omarigliptin, which is currently in phase 3 clinical development.
备注：
默克的DPP-4抑制剂西他列汀Sitagliptin在2006年10月被美国FDA批准用于治疗糖尿病。其他的DPP-4抑制剂包括维达列汀vildagliptin (2)、沙格列汀saxagliptin (3)、利格列汀linagliptin (4)和阿格列汀alogliptin (5)。
胰高血糖素样肽1(GLP-1)能抑制胰高血糖素的释放。GLP-1能被DPP-4降解成非活性形式。
2. 原文标题及出处：Discovery of Trifluoromethyl(pyrimidin-2-yl)azetidine-2-carboxamides as Potent, Orally Bioavailable TGR5 (GPBAR1) Agonists: Structure–Activity Relationships, Lead Optimization, and Chronic In Vivo Efficacy.
J. Med. Chem., 2014, 57 (8), pp 3263–3282
DOI: 10.1021/jm401731q
公司/组织：诺华
候选药物化学结构式/活性：
靶点/作用机制：TGR5激动剂
摘要原文：
Activation of the G-protein coupled receptor (GPCR) Takeda G-protein receptor 5 (TGR5), also known as G-protein bile acid receptor 1 (GPBAR1), has been shown to play a key role in pathways associated with diabetes, metabolic syndrome, and autoimmune disease. Nipecotamide 5 was identified as an attractive starting point after a high-throughput screen (HTS) for receptor agonists. A comprehensive hit-to-lead effort culminated in the discovery of 45h as a potent, selective, and bioavailable TGR5 agonist to test in preclinical metabolic disease models. In genetically obese mice (ob/ob), 45h was as effective as a dipeptidyl peptidase-4 (DPP-4) inhibitor at reducing peak glucose levels in an acute oral glucose tolerance test (OGTT), but this effect was lost upon chronic dosing.
备注：
TGR5是Gs偶联的GPCR，能被胆汁酸类特别是牛磺石胆酸激活。TGR5的激活能促使GLP-1和其他肠促胰岛素的分泌，降低单核细胞/巨噬细胞和树突细胞的脂多糖Th1细胞因子（如TNF-α和IL12）。TGR5是治疗糖尿病的有效靶点。
3. 原文标题及出处：Identification and Characterization of Small Molecule Modulators of the Epstein–Barr Virus-Induced Gene 2 (EBI2) Receptor.
J. Med. Chem., 2014, 57 (8), pp 3358–3368
DOI: 10.1021/jm4019355
公司/组织：诺华
候选药物化学结构式/活性：
靶点/作用机制：EB（Epstein-Barr）病毒诱导基因2（EBI2）受体调节剂
摘要原文：
Oxysterols have recently been identified as natural ligands for a G protein-coupled receptor called EBI2 (aka GPR183) ( Nature 2011, 475, 524; 519). EBI2 is highly expressed in immune cells ( J. Biol. Chem. 2006, 281, 13199), and its activation has been shown to be critical for the adaptive immune response and has been genetically linked to autoimmune diseases such as type I diabetes ( Nature 2010, 467, 460). Here we describe the isolation of a potent small molecule antagonist for the EBI2 receptor. First, we identified a small molecule agonist NIBR51 (1), which enabled identification of inhibitors of receptor activation. One antagonist called NIBR127 (2) was used as a starting point for a medicinal chemistry campaign, which yielded NIBR189 (4m). This compound was extensively characterized in binding and various functional signaling assays. Furthermore, we have used 4m to block migration of a monocyte cell line called U937, suggesting a functional role of the oxysterol/EBI2 pathway in these immune cells.
备注：
EBI2是G蛋白偶联受体。EBI2的激活被认为对适应性免疫反应很重要，也从遗传学角度与例如I型糖尿病等的自身免疫性疾病相关联。EBI2的调节分子对阐述EBI2的具体生理作用非常重要。目前仅有两篇关于EBI2拮抗剂GSK682753A的报道。
4. 原文标题及出处：Identification of Novel HSP90α/β Isoform Selective Inhibitors Using Structure-Based Drug Design. Demonstration of Potential Utility in Treating CNS Disorders such as Huntington’s Disease.
J. Med. Chem., 2014, 57 (8), pp 3382–3400
DOI: 10.1021/jm500042s
公司/组织：Vertex Pharmaceuticals 福泰制药
候选药物化学结构式/活性：
靶点/作用机制：HSP90α/β抑制剂，治疗中枢神经失调
摘要原文：
A structure-based drug design strategy was used to optimize a novel benzolactam series of HSP90α/β inhibitors to achieve >1000-fold selectivity versus the HSP90 endoplasmic reticulum and mitochondrial isoforms (GRP94 and TRAP1, respectively). Selective HSP90α/β inhibitors were found to be equipotent to pan-HSP90 inhibitors in promoting the clearance of mutant huntingtin protein (mHtt) in vitro, however with less cellular toxicity. Improved tolerability profiles may enable the use of HSP90α/β selective inhibitors in treating chronic neurodegenerative indications such as Huntington’s disease (HD). A potent, selective, orally available HSP90α/β inhibitor was identified (compound 31) that crosses the blood–brain barrier. Compound 31 demonstrated proof of concept by successfully reducing brain Htt levels following oral dosing in rats.
备注：
HSP90能辅助蛋白分子的正确折叠。目前大多数HSP90抑制剂都作用于N端domain的ATP结合位点，且被用于治疗癌症。而HSP90抑制剂用于其他疾病的研究受到其耐受谱的限制。
5. 原文标题及出处：Discovery of a Novel Series of Orally Active Nociceptin/Orphanin FQ (NOP) Receptor Antagonists Based on a Dihydrospiro(piperidine-4,7′-thieno[2,3-c]pyran) Scaffold
J. Med. Chem., 2014, 57 (8), pp 3418–3429
DOI: 10.1021/jm500117r
公司/组织：礼来
候选药物化学结构式/活性：
靶点/作用机制：NOP受体拮抗剂
摘要原文：
Nociceptin/OFQ (N/OFQ) is a 17 amino acid peptide that is the endogenous ligand for the ORL1/NOP receptor. Nociceptin appears to regulate a host of physiological functions such as biological reactions to stress, anxiety, mood, and drug abuse, in addition to feeding behaviors. To develop tools to study the function of nociceptin and NOP receptor, our research effort sought to identify orally available NOP antagonists. Our effort led to the discovery of a novel chemical series based on the dihydrospiro(piperidine-4,7′-thieno[2,3-c]pyran) scaffold. Herein we show that dihydrospiro(piperidine-4,7′-thieno[2,3-c]pyran)-derived compounds are potent NOP antagonists with high selectivity versus classical opioid receptors (μ, δ, and κ). Moreover, these compounds exhibit sufficient bioavailability to produce a high level of NOP receptor occupancy in the brain following oral administration in rats.
备注：
NOP受体是阿片样物质受体家族成员。属于A型GPCR。17个氨基酸多肽nociceptin/Orphanin FQ (N/OFQ)是其内源性配体。NOP受体激活与多个生理功能和行为相关，如焦虑、沮丧、紧张、心动过缓等。NOP受体是研究不同生理机制的有效靶点。
6. 原文标题及出处：Discovery of AMG 925, a FLT3 and CDK4 Dual Kinase Inhibitor with Preferential Affinity for the Activated State of FLT3
J. Med. Chem., 2014, 57 (8), pp 3430–3449
DOI: 10.1021/jm500118j
公司/组织：Amgen
候选药物化学结构式/活性：
靶点/作用机制：FLT3/CDK4双靶点激酶抑制剂
摘要原文：
We describe the structural optimization of a lead compound 1 that exhibits dual inhibitory activities against FLT3 and CDK4. A series of pyrido[4′,3′:4,5]pyrrolo[2,3-d]pyrimidine derivatives was synthesized, and SAR analysis, using cell-based assays, led to the discovery of 28 (AMG 925), a potent and orally bioavailable dual inhibitor of CDK4 and FLT3, including many FLT3 mutants reported to date. Compound 28 inhibits the proliferation of a panel of human tumor cell lines including Colo205 (Rb+) and U937 (FLT3WT) and induced cell death in MOLM13 (FLT3ITD) and even in MOLM13 (FLT3ITD, D835Y), which exhibits resistance to a number of FLT3 inhibitors currently under clinical development. At well-tolerated doses, compound 28 leads to significant growth inhibition of MOLM13 xenografts in nude mice, and the activity correlates with inhibition of STAT5 and Rb phosphorylation.
备注：
CDK4是FLT3下游分子，与急性髓性白血病相关。FLT3/CDK4双靶点激酶抑制剂在AML治疗上具有显著优势，通过同时调节两个协同的失调靶点提高耐受性。
7. 原文标题及出处：Discovery of 6-Phenylpyrimido[4,5-b][1,4]oxazines as Potent and Selective Acyl CoA
iacylglycerol Acyltransferase 1 (DGAT1) Inhibitors with in Vivo Efficacy in Rodents
J. Med. Chem., 2014, 57 (8), pp 3464–3483
DOI: 10.1021/jm500135c
公司/组织：Amgen
候选药物化学结构式/活性：
靶点/作用机制：DGAT1抑制剂
摘要原文：
The discovery and optimization of a series of acyl CoA:diacylglycerol acyltransferase 1 (DGAT1) inhibitors based on a pyrimido[4,5-b][1,4]oxazine scaffold is described. The SAR of a moderately potent HTS hit was investigated resulting in the discovery of phenylcyclohexylacetic acid 1, which displayed good DGAT1 inhibitory activity, selectivity, and PK properties. During preclinical toxicity studies a metabolite of 1 was observed that was responsible for elevating the levels of liver enzymes ALT and AST. Subsequently, analogues were synthesized to preclude the formation of the toxic metabolite. This effort resulted in the discovery of spiroindane 42, which displayed significantly improved DGAT1 inhibition compared to 1. Spiroindane 42 was well tolerated in rodents in vivo, demonstrated efficacy in an oral triglyceride uptake study in mice, and had an acceptable safety profile in preclinical toxicity studies.
备注：
对甘油三酯合成的调节与对多种疾病的治疗相关，包括肥胖、II型糖尿病、血脂异常、肝性脂肪变性、代谢综合征和冠心病。DGAT（酯酰辅酶A：二酰甘油转移酶）催化甘油三酯的最后且关键的一步。
8. 原文标题及出处：
Discovery of Selective 4-Amino-pyridopyrimidine Inhibitors of MAP4K4 Using Fragment-Based Lead Identification and Optimization
J. Med. Chem., 2014, 57 (8), pp 3484–3493
DOI: 10.1021/jm500155b
公司/组织：Genentech Inc
候选药物化学结构式/活性：
靶点/作用机制：MAP4K4抑制剂
摘要原文：
Mitogen-activated protein kinase kinase kinase kinase 4 (MAP4K4) is a serine/threonine kinase implicated in the regulation of many biological processes. A fragment-based lead discovery approach was used to generate potent and selective MAP4K4 inhibitors. The fragment hit pursued in this article had excellent ligand efficiency (LE), an important attribute for subsequent successful optimization into drug-like lead compounds. The optimization efforts eventually led us to focus on the pyridopyrimidine series, from which 6-(2-fluoropyridin-4-yl)pyrido[3,2-d]pyrimidin-4-amine (29) was identified. This compound had low nanomolar potency, excellent kinase selectivity, and good in vivo exposure, and demonstrated in vivo pharmacodynamic effects in a human tumor xenograft model.
备注：
MAP4K4参与到多个信号通路中。MAP4K4与多个生理过程以及病理过程相关，包括新陈代谢、炎症、神经变性、癌症。对MAP4K4的抑制有助于对这些疾病的治疗。
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